Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial.

The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m2 , HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.

A randomized, open-label, active comparator trial assessing the effects of 26 weeks of liraglutide or sitagliptin on cardiovascular function in young obese adults with type 2 diabetes.

AIM: To compare the effects of a glucagon-like peptide-1 receptor agonist and a dipeptidyl peptidase-4 inhibitor on magnetic resonance imaging-derived measures of cardiovascular function. MATERIALS AND METHODS: In a prospective, randomized, open-label, blinded endpoint trial liraglutide (1.8 mg) and sitagliptin (100 mg) were compared in asymptomatic, non-insulin treated young (aged 18-50 years) adults with obesity and type 2 diabetes. The primary outcome was difference in circumferential peak early diastolic strain rate change (PEDSR), a biomarker of cardiac diastolic dysfunction 26 weeks after randomization. Secondary outcomes included other indices of cardiac structure and function, HbA1c and body weight. RESULTS: Seventy-six participants were randomized (54% female, mean ± SD age 44 ± 6 years, diabetes duration 4.4 years, body mass index 35.3 ± 6.1 kg m-2 ), of whom 65% had ≥1 cardiovascular risk factor. Sixty-one participants had primary outcome data available. There were no statistically significant between-group differences (intention-to-treat; mean [95% confidence interval]) in PEDSR change (-0.01 [-0.07, +0.06] s-1 ), left ventricular ejection fraction (-1.98 [-4.90, +0.94]%), left ventricular mass (+1.14 [-5.23, +7.50] g) or aortic distensibility (-0.35 [-0.98, +0.28] mmHg-1 × 10-3 ) after 26 weeks. Reductions in HbA1c (-4.57 [-9.10, -0.37] mmol mol-1 ) and body weight (-3.88 [-5.74, -2.01] kg) were greater with liraglutide. CONCLUSION: There were no differences in cardiovascular structure or function after short-term use of liraglutide and sitagliptin in younger adults with obesity and type 2 diabetes. Longer studies in patients with more severe cardiac dysfunction may be necessary before definitive conclusions can be made about putative pleiotropic properties of incretin-based therapies.

Skin autofluorescence, a non-invasive marker of advanced glycation end products: clinical relevance and limitations.

Advanced glycation end products (AGEs) are protein-bound compounds derived from glycaemic and oxidative stress that contain fluorescent properties, which can be non-invasively measured as skin autofluorescence (SAF) by the AGE Reader. SAF has been demonstrated to be a biomarker of cumulative skin AGEs and potentially may be a better predictor for the development of chronic complications and mortality in diabetes than glycated haemoglobin A1c. However, there are several confounding factors that should be assessed prior to its broader application: these include presence of other fluorescent compounds in the skin that might be measured (eg, fluorophores), skin pigmentation and use of skin creams. The aim of this article is to provide a theoretical background of this newly developed method, evaluate its clinical relevance and discuss the potential confounding factors that need further analysis.

The potential benefit of non-purified islets preparations for islet transplantation.

Since the advent of islet transplantation, there has been a significant emphasis on the importance of islet purity despite an inevitable associated loss of islet mass during the purification process. One of the key elements of the 'Edmonton Protocol' for islet transplantation published in 2000 was an emphasis on the need for sequential transplants of highly purified islets (averaging 24% beta cell purity) and the close correlation between the numbers of islets transplanted and the success of the procedure. However, the emphasis on islet purity may warrant further consideration as auto transplantation of non-purified islets currently provides the most successful insulin independence rates within the field of islet transplantation. While the role of auto and allo immunity could contribute to the differences in the success rates it is clear that within the clinical setting, significant acinar and ductal contamination is well tolerated. However, one could go further and hypothesize that extra-insular tissue including acinar tissue, ductal tissue, peri-pancreatic lymph nodes and vascular tissue actually confer an advantage to islet survival/function and may even contribute to the insulin secreting capacity of the graft post transplant. As such this review will assess the influence of extra-insular pancreatic tissue on the results of islet transplantation based on published evidence and will also explore the possibility that non-islet pancreatic cells are capable of differentiating into a beta cell phenotype in vivo contributing to an ongoing regeneration of endocrine mass during the period following transplantation.

Use of the recanalised umbilical vein for islet autotransplantation following total pancreatectomy.

INTRODUCTION: Islet autotransplantation requires access to the portal vein or tributaries. We originally infused islets into the liver via the middle or right colic veins, but since 2005 we have used the recanalised umbilical vein. Here, we describe the technique, the advantages and the early results achieved. MATERIALS AND METHODS: After removal of the pancreas and restoration of the biliary and enteric continuity, the ligamentum teres is transected. The obliterated umbilical vein is identified and recanalised with Bakes dilators giving access to the left portal vein. A Vygon® Nutricath 'S' 11-Fr catheter is inserted and used for the islet infusion. If the ligamentum teres is to be exteriorised for postoperative measurements or subsequent access, it is pulled through a 10-mm laparoscopic port in the epigastrium, sutured to the skin and covered with a dressing. RESULTS: We have used this approach in 17 patients and exteriorised the falciform ligament in 4. There have been no intra- or postoperative complications. CONCLUSIONS: The recanalised umbilical approach is safe and allows for venous sampling and postoperative measurements of the portal pressure. Under local anaesthetic, the umbilical vein can be approached above the umbilicus and exteriorised if repeated transplants are required for allograft patients. and IAP.

Total pancreatectomy with islet autotransplantation: an overview.

Pain control is one of the most challenging aspects in the management of chronic pancreatitis. Total pancreatectomy can successfully relieve the intractable abdominal pain in these patients but will inevitably result in insulin-dependent diabetes. Islet autotransplantation aims to preserve, as far as possible, the insulin secretory function of the islet cell mass thereby reducing (or even removing) the requirement for exogenous insulin administration after a total pancreactomy. Despite the relatively small number of centres able to perform these procedures, there are important technical variations in the details of their approaches. The aim of this review is to provide details of the current surgical practice for total pancreatectomy combined with islet autotransplantation, and outline the potential advantages and disadvantages of the variations adopted in each centre.

Ultrasound changes within the liver after total pancreatectomy and intrahepatic islet cell autotransplantation.

OBJECTIVE: Intrahepatic infusion is the most common method of islet autotransplantation. Structural and functional changes within the liver may result from a number of factors, including embolization of the terminal branches of the portal vein, the effects of high insulin concentration on surrounding hepatocytes or responses to the death of admixed exocrine tissue. Awareness of the potential changes in the appearance of the liver on ultrasonography (USS), together with an assessment of liver function, is important in the postoperative surveillance of these patients. METHODS: We retrospectively reviewed 83 patients who underwent total pancreatectomy between 1993 and 2006. Thirty-three patients had total pancreatectomy alone (control group) and 50 patients underwent total pancreatectomy and islet autotransplantation (islet group). The islets were infused into the left lobe of the liver through the middle colic or recannalated umbilical vein. All patients underwent USS as part of their hepaticojejunostomy surveillance (initially every 6 months and then yearly). RESULTS: "Echogenic nodularity" of the liver was observed in 25% of the islet group of patients and in none of the control group patients (P=0.03). These USS changes occurred from 6 to 12 months after islet autotransplantation and were not associated with any significant loss of liver function or increase in insulin requirements. The islet group had significantly less insulin requirement compared with the control group (P<0.01). CONCLUSION: Echogenicity with a nodular appearance is a common ultrasonographic finding in the liver after intrahepatic islet autotransplantation. These changes do not seem to adversely affect liver function or insulin requirement. Appreciating these changes is important to avoid misinterpretation or over-interpretation of postoperative USS images.

Differential effects of curcumin on cryopreserved versus fresh primary human hepatocytes.

Curcumin (CUR) is a major component of a dietary spice derived from the roots of Curcuma longa. It has strong antioxidant activities and hepatoprotective properties. Primary human hepatocytes are clinically used in transplantation or in bioartificial liver devices for the treatment of patients with liver failure. Fresh and cryopreserved hepatocytes are also used in vitro for the study of drugs in pharmacotoxicology. We aimed to assess whether CUR could improve human liver cell viability and prevent oxidative damage responsible for large cell loss during cell preparation. Our study showed beneficial effects of CUR (25 microM) on freshly isolated human hepatocytes, increasing significantly metabolic activity of viable attached cells when seeded with CUR for 24 h. However CUR added during the cell isolation process did not have any significant impact on cell isolation outcomes or on cryopreservation outcomes. Conversely, CUR added during the thawing of frozen cells had a negative effect on the cell attachment capacity of hepatocytes that were cryopreserved in the presence or absence of CUR. In conclusion, although having positive effects on viability and challenge of oxidative stress on cultured human hepatocytes, CUR had no beneficial effect on cell isolation or cryopreservation outcomes.

Elevated Levels of Alpha Cells Emanating from the Pancreatic Ducts of a Patient with a Low BMI and Chronic Pancreatitis.

Chronic pancreatitis (CP) is an inflammatory disease that causes progressive damage to the pancreatic parenchyma with irreversible morphological changes and fibrotic replacement of the gland. The risk factors associated with developing CP have been described as toxic (e.g., alcohol and tobacco); idiopathic (e.g., unknown); genetic, autoimmune, recurrent acute pancreatitis, and obstructive (the TIGAR-O system). Upon histological screening of the pancreata from a cohort of CP patients who had undergone pancreatectomy for the treatment of intractable pain in Leicester, UK, one sample showed a striking change in the morphological balance toward an endocrine phenotype, most notably there was evidence of substantial α cell genesis enveloping entire cross sections of ductal epithelium and the presence of α cells within the ductal lumens. This patient had previously undergone a partial pancreatectomy, had severe sclerosing CP, an exceptionally low body mass index (15.2), and diabetes at the time the pancreas was removed, and although these factors have been shown to induce tissue remodeling, such high levels of α cells was an unusual finding within our series of patients. Due to the fact that α cells have been shown to be the first endocrine cell type that emerges during islet neogenesis, future research profiling the factors that caused such marked α cell genesis may prove useful in the field of islet transplantation.

Immunohistochemical evidence that culture in the high aspect rotating vessel can up-regulate hormone expression in growth dedifferentiated PHHI-derived islet cells.

Islet cells derived from patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) have the ability to grow readily in simple culture media. However, as with primary islets and cell lines, they lose hormone expression upon growth. In this study, we have investigated the role of three-dimensional cell-to-cell contact in the reinitiation of hormone expression in growth dedifferentiated PHHI-derived cells. Two main methods of cell aggregation were studied; the promotion of pseudoislets through petri dish culture and the creation of cell aggregates in the microgravity environment of the high aspect ratio vessel (HARV). Immunohistochemical analysis and ELISA assay showed that petri dish culture did not re-establish endocrine expression in any of the five cultures tested. However, through HARV technology, we have demonstrated that it is possible to reactivate insulin, glucagon, somatostatin, and GAD expression in PHHI-derived cells that had previously stopped expressing these markers. These results indicate that the unique environment of the HARV can be conducive to the upregulation of endocrine expression of islet-derived cells and optimization of culture conditions may prove useful in the sphere of beta cell proliferation.

The association between depressive symptoms and insulin resistance, inflammation and adiposity in men and women.

INTRODUCTION: Depression has been shown to be associated with elevated leptin levels, low-grade inflammation and insulin resistance. These derangements are often measured in mixed gender cohorts despite the different body compositions and hormonal environments of men and women and gender-specific prevalence and responses to depression. METHODS: A cross-sectional analysis was carried out on a cohort of 639 participants from the ADDITION-Leicester dataset to assess differences in markers of diabetes risk, cardiovascular risk and inflammation in depressed and non-depressed individuals. Depressive symptoms were determined using the WHO (Five) well-being index. Multivariate linear and logistic regression analyses were adjusted for age, sex, ethnicity, body mass index, smoking, social deprivation and activity levels for continuous and binary variables respectively. Further analysis included stratifying the data by gender as well as assessing the interaction between depression and gender by including an interaction term in the model. RESULTS: Women with depressive symptoms had a 5.3% larger waist circumference (p = 0.003), 28.7% higher HOMA IR levels (p = 0.026), 6.6% higher log-leptin levels (p = 0.01) and 22.37% higher TNF-α levels (p = 0.015) compared with women without. Conversely, depressive symptoms in men were associated with 7.8% lower body fat % (p = 0.015) but 48.7% higher CRP levels (p = 0.031) compared to men without. However, interaction analysis failed to show a significant difference between men and women. CONCLUSIONS: Depressive symptoms are associated with metabolic derangements. Whilst women tended to show elevations in biomarkers related to an increased risk of type 2 diabetes (HOMA IR, leptin and TNF-α), men showed a marked increase in the cardiovascular disease risk biomarker CRP. However, perhaps due to the cohort size, interaction analysis did not show a significant gender difference.

Effect of the PPARG2 Pro12Ala Polymorphism on Associations of Physical Activity and Sedentary Time with Markers of Insulin Sensitivity in Those with an Elevated Risk of Type 2 Diabetes.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is an important regulator of metabolic health and a common polymorphism in the PPAR-γ2 gene (PPARG2) may modify associations between lifestyle behaviour and health. OBJECTIVE: To investigate whether the PPARG2 Pro12Ala genotype modifies the associations of sedentary behaviour and moderate-to-vigorous intensity physical activity (MVPA) with common measures of insulin sensitivity. METHODS: Participants with a high risk of impaired glucose regulation were recruited, United Kingdom, 2010-2011. Sedentary and MVPA time were objectively measured using accelerometers. Fasting and 2-hour post-challenge insulin and glucose were assessed; insulin sensitivity was calculated using Matsuda-ISI and HOMA-IS. DNA was extracted from whole blood. Linear regression examined associations of sedentary time and MVPA with insulin sensitivity and examined interactions by PPARG2 Pro12Ala genotype. RESULTS: 541 subjects were included (average age = 65 years, female = 33%); 18% carried the Ala12 allele. Both sedentary time and MVPA were strongly associated with HOMA-IS and Matsuda-ISI after adjustment for age, sex, ethnicity, medication, smoking status and accelerometer wear time. After further adjustment for each other and BMI, only associations with Matsuda-ISI were maintained. Every 30 minute difference in sedentary time was inversely associated with a 4% (0, 8%; p = 0.043) difference in Matsuda-ISI, whereas every 30 minutes in MVPA was positively associated with a 13% (0, 26%; p = 0.048) difference. The association of MVPA with Matsuda-ISI was modified by genotype (p = 0.005) and only maintained in Ala12 allele carriers. Conversely, sedentary time was not modified by genotype and remained inversely associated with insulin sensitivity in Pro12 allele homozygotes. CONCLUSION: The association of MVPA with Matsuda-ISI was modified by PPARG2 Pro12Ala genotype with significant associations only observed in the 18% of the population who carried the Ala12 allele, whereas associations with sedentary time were unaffected.

The socio-economic impact of chronic pancreatitis: a systematic review.

RATIONALE, AIMS AND OBJECTIVES: Chronic pancreatitis (CP) is a progressive inflammatory disorder with pain being the most frequent symptom. It is associated with loss of function, pancreatogenic diabetes and digestive enzyme deficiency. The impact of local complications and loss of pancreatic function results in unknown and unreported costs. This study attempts to identify both the direct and indirect costs associated with CP. METHODS: A MEDLINE literature review was performed for all relevant articles relating to any aspect of direct and indirect costs as a result of CP. RESULTS: In the UK, there are 12,000 admissions per annum of patients with CP at an estimated cost of £55.8 million. The costs for loss of pancreatic function are estimated at £45-90 million and $75.1 million for endocrine and exocrine function, respectively. Chronic pain contributes $638 million per year in costs. The protracted course of CP and paucity of monetary data make quantifying direct and indirect costs difficult. An estimate of direct and indirect costs is at £285.3 million per year. This equates to £79,000 per person per year. CONCLUSIONS: Patients with CP consume a disproportionately high volume of resources.

Patient satisfaction and cost-effectiveness following total pancreatectomy with islet cell transplantation for chronic pancreatitis.

OBJECTIVES: Chronic pancreatitis (CP) results in an extremely poor quality of life and substantially increases health care utilization. Few data exist regarding the cost-effectiveness of surgical treatment for CP. METHODS: This article examined the cost-effectiveness of total pancreatectomy (TP) with islet cell autotransplantation (IAT) for CP. RESULTS: Sixty patients undergoing TP + IAT and 37 patients undergoing TP were identified. Surgery resulted in significant reduction in opiate use, frequency of hospital admissions, and length of stay as well as visual analog scale scores for pain. Total pancreatectomy + IAT resulted in longer survival than TP alone (16.6 vs 12.9 years); 21.6% of patients with TP + IAT were insulin-independent, and those requiring insulin have reduced daily requirements compared with those having TP alone (22 vs 35 IU). The cost of TP + IAT with attendant admission and analgesia costs over the 16-year survival period was £110,445 compared with £101,608 estimated 16-year costs if no TP + IAT was undertaken. CONCLUSIONS: Total pancreatectomy + IAT is effective in improving pain and reducing analgesia. Islet cell transplantation offers the chance of insulin independence and results in lower insulin requirements, as well as conferring a survival advantage when compared with TP alone. Total pancreatectomy + IAT is cost-neutral when compared with nonsurgical or segmental surgical therapy.

The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential.

Omega-3 fatty acid (omega-3 FA) consumption has long been associated with a lower incidence of colon, breast and prostate cancers in many human populations. Human trials have demonstrated omega-3 FA to have profound anti-inflammatory effects in those with cancer. In vitro and small animal studies have yielded a strong body of evidence establishing omega-3 FA as having anti-inflammatory, anti-apoptotic, anti-proliferative and anti-angiogenic effects. This review explores the evidence and the mechanisms by which omega-3 FA may act as angiogenesis inhibitors and identifies opportunities for original research trialling omega-3 FAs as anti-cancer agents in humans. The conclusions drawn from this review suggest that omega-3 FAs in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found principally in oily fish have potent anti-angiogenic effects inhibiting production of many important angiogenic mediators namely; Vascular Endothelial Growth Factor (VEGF), Platelet-Derived Growth Factor (PDGF), Platelet-Derived Endothelial Cell Growth Factor (PDECGF), cyclo-oxygenase 2 (COX-2), prostaglandin-E2 (PGE2), nitric oxide, Nuclear Factor Kappa Beta (NFKB), matrix metalloproteinases and beta-catenin.

Total pancreatectomy with and without islet cell transplantation for chronic pancreatitis: a series of 85 consecutive patients.

OBJECTIVES: This study examined 85 consecutive patients undergoing total pancreatectomy (+/-islet cell transplant), examining pain relief, insulin requirements, and glycemic control postoperatively. METHODS: A prospective database of all patients undergoing total pancreatectomy for chronic pancreatitis was used to record preoperative and postoperative details from 1996 to 2006. RESULTS: There were 3 postoperative deaths (1 islet recipient and 2 nonislet patients). The median number of acute admissions for pain fell from 5 to 2 after pancreatectomy, and the median length of stay from 6.2 days to 3.3 days. At 12 months postoperatively, the number of patients on regular opiate analgesia fell from 90.6% to 40.2% and by 5 years to 15.9%. There was a significant reduction in the patients' visual analogue pain score after surgery from 9.7 to 3.7 (P < 0.001). Five patients were insulin independent at 5 years. Median 24-hour insulin requirements were significantly lower in the islet group (15.5 vs 40 units at 5 years postoperatively; P < 0.001). CONCLUSIONS: Total pancreatectomy is effective in reducing pain and dependence on opioid analgesia in patients with chronic pancreatitis. The addition of an islet cell transplant results in a reduction in 24-hour insulin demands, as well as potentially achieving insulin independence.

Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function.

UNLABELLED: Total pancreatectomy is considered the final resort in the treatment of chronic pancreatitis; however, here we show that simultaneous islet autotransplantation can abrogate the onset of diabetes. METHODS: : In Leicester, 46 patients have now undergone total pancreatectomy with immediate islet auto transplant, and they have received a median of 2246 islet equivalent (IEQ)/kg body weight (range, 405-20,385 IEQ/kg body weight). RESULTS: : Twelve patients have shown periods of insulin independence, for a median of 16.5 months (range, 2-63 months), and 5 remain insulin independent. Over the 10 years of follow-up, there has been a notable increase in insulin requirement per kilogram per day, and percentage of glycosylated hemoglobin levels have increased significantly (r = 0.66, P = 0.01). However, 100% of patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide values recorded at 10 years after transplantation, 1.44 (range, 1.09-1.8 ng/mL) and 2.86 ng/mL (range, 1.19-4.53 ng/mL), respectively, suggest significant graft function in the long term. In addition, median serum creatinine has increased very little after the operation (71 nmol/L [range, 49-125 nmol/L] atpreoperation vs 76.5 nmol/L [range 72-81 nmol/L] at year 10), suggesting no diabetic nephropathy. CONCLUSIONS: : Although there is a notable decline in islet function after islet auto transplant, there is still evidence of significant long-term insulin secretion and possible protection against diabetic complications.

Growth restriction and exendin 4 promote endocrine expression in cultured islet cells derived from patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI).

Islets derived from patients with persistent hyperinsulinemic hypoglycemia of infancy, PHHI, show a significant capacity to proliferate in vitro without the addition of growth factors. However, as with other differentiated cells, PHHI-derived islet cells show a loss of differentiated function with repeated subculture. Here, we have investigated methods of extending the differentiated function of PHHI-derived endocrine cells following in vitro expansion. The experiments were carried out on 13 primary pancreatic cell cultures from patients with PHHI, the majority of which (n = 11) were glucose unresponsive--a distinctive feature of PHHI disease. After a 20-day period of cell expansion in 10% FCS, cells were switched to media containing varying concentrations of FCS with or without exendin 4 and endocrine function was measured using ELISA and RT-PCR for insulin and PDX-1. Switching the expanded cultures to low serum was shown to slow cell division while maintaining the residual differentiated endocrine characteristics of all the cultures tested. Exendin 4 was shown to further enhance the improved insulin secretion shown by low serum cultures, although in glucose nonresponsive cells, this was at the expense of insulin stores. However, we did observe that exendin 4 could upregulate insulin secretion, insulin storage, and PDX-1 expression in glucose responsive PHHI cultures.